Ocular treatment using cyclosporin-A derivatives

ABSTRACT

A method of treating a disorder in an eye, for example, an aqueous deficient dry eye state, phacoanaphylactic endophthalmitis, or uveitis, is provided. The method generally includes administering a therapeutically effective amount of a certain cyclosporin A derivative topically to the affected eye. The derivative may be administered as a solution, suspension or ointment in a pharmaceutically acceptable excipient.

The present invention generally relates to treatment of ocular diseasesand disorders and more specifically relates to a method for treatment ofaqueous deficient dry-eye state, phacoanaphylaxis endophthalmitis anduveitis using certain cyclosporin derivatives.

The exposed part of a normal eye is covered by a thin tear film. Thepresence of a continuous tear film is important for the well-being ofthe corneal and conjunctival epithelium and provides the cornea with anoptically high quality surface. In addition, the aqueous part of thetear film acts as a lubricant to the eyelids during blinking of thelids. Furthermore, certain enzymes contained in the tear fluid, forexample immunoglobin A, lysozyme and beta lysin, are known to havebacteriostatic properties.

A sound lacrimal system functions to form and maintain a properlystructured, continuous tear film. The lacrimal apparatus consists of thesecretory system (the source), the distribution system, and theexcretory system (the sink). In the secretory system, aqueous tears aresupplied by main and accessory lacrimal glands. The bulk of the tearfilm is made of such aqueous tear. The continuous production anddrainage of aqueous tear is important in maintaining the corneal andconjunctival epithelium in a moist state, in providing nutrients forepithelial respiration, in supplying bacteriostatic agents and incleaning the ocular surface by the flushing action of tear movement.

Abnormalities of the tear film include an absolute or partial deficiencyin aqueous tear production (keratoconjunctivitis sicca, or KCS).

In relatively mild cases, the main symptom of KCS is a foreign bodysensation or a mild scratchiness. This can progress to become aconstant, intense burning or irritative sensation that can bedebilitating to a patient.

More severe forms can progress to the development of filamentarykeratisis, a painful condition characterized by the appearance ofnumerous strands or filaments attached to the corneal surface. Evidencesuggests that these filaments represent breaks in the continuity ofnormal corneal epithelial cells. The shear created by lid motion pullsthese filaments, causing pain. Management of this stage of KCS is verydifficult.

A frequent complication of KCS is secondary infection. Severalbreakdowns in the eye's normal defense mechanisms seem to occur,presumably attributable to a decrease in the concentration ofantibacterial lysozyme in the aqueous tears of a patient suffering fromKCS.

Although KCS can develop in the absence of any other overt systemabnormality, there is a frequent association of KCS with systemicdisease. KCS can occur as part of a larger systemic involvement known asSjogren's syndrome. This classically consists of dry eyes, dry mouth andarthritis.

Histologically, in KCS (as part of Sjogren's syndrome or in isolation),the initial changes seen in the lacrimal glands are those of focallymphocytic and plasma cell infiltrates associated with degeneration ofglandular tissue. These changes resemble those seen in autoimmunedisease in other tissue, giving rise to the speculation that KCS has anautoimmune basis.

Sjogren's syndrome is recognized as an exocrine gland dysfunction.Characteristically, the lacrimal glands show a mononuclear cellinfiltration that ultimately leads to destruction of the glandularstructure.

Conventional treatment of KCS is symptomatic. Normally,aqueous-deficient dry eye states are treated by supplementation of thetears with artificial tear substitutes. However, relief is limited bythe retention time of the administered artificial tear solution in theeye. Typically, the effect of an artificial tear solution administeredto the eye dissipates within about thirty to forty-five minutes. Thus,the effect of such products, while soothing initially, does not lastlong enough. The patient is inconvenienced by the necessity of repeatedadministration of artificial tear solution in the eye as needed tosupplement the normal tears. Moreover, such treatment merely acts toalleviate the symptoms of the dry eye state and does not cure anyunderlying disorders or causes of the dry eye state.

Histologic studies of the lacrimal glands in patients suffering fromSjogren's syndrome have shown some evidence of lacrimal glandinflammation. Such inflammation may be simply due to the normal aging ofthe patient. It has been suggested that the use of anti-inflammatoryagents might serve to decrease the glandular inflammation. The systemicuse of corticosteroids has been advocated in these conditions. However,the merit of systemic corticosteroids in dry eye states has not beenestablished. In most dry eye cases, the hazards of long term use ofanti-inflammatory agents would seem to outweigh their potential merit.

Surgical procedures have also been suggested in the management of dryeye states. Where there has been significant conjunctival destruction,mucous membrane transplants have been advocated. It has also beensuggested that parotid (saliva) duct transplantation can be useful inthe management of dry eyes. However, surgical alterations to combat dryeye conditions constitute a dramatic remedy and any benefit resultingfrom these alterations is questionable.

It has also been suggested to administer orally a dilute solution ofpilocarpine to stimulate the autonomic nervous system to effectincreased aqueous tear production. This method of treatment has not metwith universal favor because of many unpleasant side effects of ingestedpilocarpine.

Animal models of Sjogren's syndrome have been instrumental in basicophthalmic research. A Sjogren's-like disease has been found in dogswith systemic luperythematosus. This disease, which may be referred toas canine KCS, is a common, chronic, progressive, and potentiallyblinding disease. A continuum of corneal and conjunctival lesions ensuesfrom the dry eye state. The cause of canine KCS is often not identified.Usually canine KCS is not an isolated ophthalmic disease. It has beenspeculated in Kaswan et al., Am. J. Vet. Res. 46, 376-383 (1985), thatmost cases of canine KCS occur via autoimmune mechanisms.

Other diseases of the eye include phacoanaphylactic endophthalmitis anduveitis. These diseases can be located throughout the eye, in both theposterior and anterior chambers of the eye as well as in the vitreousbody.

Uveitis, the inflamation of the uvea, is responsible for about 10% ofthe visual impairment in the United States. Phacoanaphylacticendophthalmitis is a human autoimmune disease.

Panuveitis refers to inflamation of the entire uveal (vascular) layer ofthe eye. Posterior uveitis generally refers to chorioentinitis, andanterior uveitis refers to iridocyclitis. The inflammatory products(i.e. cells, fibrins, excess proteins) of these inflammations arecommonly found in the fluid spaces if the eye, i.e. anterior chamber,posterior chamber and vitreous space as well as infiltrating the tissueintimately involved in the inflammatory response. Uveitis may occurfollowing surgical or traumatic injury to the eye; as a component of anautoimmune disorder, i.e. rheumatoid arthritis, Behcet's disease,ankylosing spondylitis, sarcoidosis; as an isolated immune mediatedocular disorder, i.e. pars planitis, iridocyclitis etc., unassociatedwith known etiologies; and following certain systemic diseases whichcause antibody-antigen complexes to be deposited in the uveal tissues.Together these disorders represent the non-infectious uveitities.

The normal eye is protected from immune surveillance by blood barrierswhich do not allow free migration of cells or proteins into the eye.When the eye is injured or when vasculitis occurs, the internal ocularstructures are exposed to the general immune system and frequentlyillicit autoimmune responses.

Phacoanaphylaxis is a severe form of uveitis in which the lens in thecausative antigen. The lens proteins are normally secluded by the lenscapsule since before birth. When these proteins are released into theeye by injury or by surgery or occasionally during cataract development,they can become intensely antigenic and incite an autoimmune response.If the response is moderate it is seen as chronic uveitis. If it is veryfast in progression the eye becomes seriously inflamed in all segments.This latter response is named phacoanaphylaxis.

Methylthio-substituted cyclosporin A and other alkylthio-substitutedcyclosporin A derivatives have been described in PCT application nos.98-379455, 98-379456 and 98-379457 and have been found to be activeagainst certain retroviruses, especially AIDS (acquired immunodeficiencysyndrome) and ARC (AIDS-related complex) when administered orally,parenterally, rectally or by inhalation. In addition, they havegenerally been found to have only a very weak immunosuppressant action,and to show anti-retroviral activity at non-cytotoxic and non-cytostaticconcentrations. These compounds are claimed to have a synergistic actionwith other agents active against retrovirus (such as inhibitors ofreverse transcriptase, protease, integrase, HIV replication andnucleocapside).

Although these compounds are claimed to be effective againstretroviruses, it has not been heretobefore suggested to administer anyof these compounds to a patient in order to treat the ocular diseasesdescribed hereinabove. The present invention provides a method oftreating a patient affected with such an ocular disorder by topicallyapplying one or more of these compounds to the diseased eye.

SUMMARY OF THE INVENTION

Accordingly, a method in accordance with the present invention generallycomprises the step of administering to an eye, a therapeuticallyeffective amount of a compound selected from the group consisting of((R)-methylthio-Sar)³-(4′-hydroxy-MeLeu) cyclosporin A,((R)-(Cyclo)alkylthio-Sar)³-(4′-hydroxy-MeLeu)⁴-cyclosporin A, and((R)-(Cyclo)alkylthio-Sar)³-cyclosporin A derivatives of the formulasdescribed below, in order to treat an ocular disorder in the eye, forexample, an aqueous deficient dry eye state, uveitis, orphacoanaphylactic endophthalmitis. The cyclosporin A derivativesutilized in the method of the present invention are disclosed inpublished PCT patent applications nos. 98-379455, 98-379456, and98-379457, entitled New Methylthio-substituted Cyclosporin Aderivative—Active Against Retro-viruses and Having Only WeakImmunosuppressant Action, Used in Treatment of AIDS, NewAlkylthio-substituted Cyclosporin A derivatives—Active AgainstRetro-viruses and Having Only Weak Immunosuppressant Action, Used inTreatment of AIDS, and New Alkylthio-substituted Cyclosporin Aderivatives—Active Against Retro-viruses and Having Only WeakImmunosuppressant Action, Used for Treating AIDS, respectively, whichare hereby incorporated by reference in their entirety.

The objects and advantages of the present invention will be more clearlyunderstood and appreciated with reference to the following detaileddescription.

DETAILED DESCRIPTION

The present invention provides a method for the treatment of uveitis andphacoanaphylactic endophthalmitis, in a patient suffering therefrom, aswell as an aqueous deficient dry eye state, by topical application tothe affected eye, of a cyclosporin derivative, selected from the groupconsisting of ((R)-methylthio-Sar)³-(4′-hydroxy-MeLeu) cyclosporin A,((R)-(Cyclo)alkylthio-Sar)³-(4′-hydroxy-MeLeu)⁴-cyclosporin A, and((R)-(Cyclo)alkylthio-Sar)³-cyclosporin A derivatives described below.

These cyclosporin derivatives are represented by the following generalformulas (I), (II), and (III) respectively:

wherein Me is methyl; Alk is 2-6C alkylene or 3-6C cycloalkylene; R isOH, COOH, alkoxycarbonyl, —NR₁ R₂ or —N(R₃)—(CH₂)—NR₁R₂; wherein R₁,R₂is H, alkyl, 3-6C cycloalkyl, phenyl (optionally substituted by halo,alkoxy, alkoxycarbonyl, amino, alkylamino or dialkylamino), benzyl orsaturated or unsaturated heterocyclyl having 5 or 6 members and 1-3heteroatoms; or NR₁R₂ is a 5 or 6 membered heterocycle which may containa further N, O or S heteroatom and may be alkylated; R₃ is H or alkyland n is 2-4; and alkyl moieties contain 1-4C.

In accordance with the present invention, the cyclosporin A derivativesmay be applied to an affected eye in any efficacious concentration,e.g., 0.01 to saturation (e.g. greater than 20 weight percent) in apharmaceutically acceptable excipient. From 0.01 to 50 weight percent,preferably from 0.1 to 20 weight percent, of cyclosporin A derivativesin a pharmaceutically acceptable excipient may be used. Suchpharmaceutically acceptable excipients are, for example, animal oil,vegetable oil, an appropriate organic or aqueous solvent, an artificialtear solution, a natural or synthetic polymer, or an appropriatemembrane to encapsulate the cyclosporin A derivative.

Specific examples of these pharmaceutically acceptable excipients areolive oil, arachis oil, castor oil, mineral oil, petroleum jelly,dimethyl sulphoxide, chremophor, Miglyol 182 (commercially availablefrom Dynamit Nobel Kay-Fries Chemical Company, Mont Vale, N.J.), analcohol (e.g. ethanol, n-propyl alcohol, or iso-propyl alcohol),liposomes or liposome-like products or a silicone fluid. Preferredexcipients are dimethyl sulphoxide and olive oil. Mixtures of at leasttwo of any suitable excipients may be used.

Examples of artificial tear excipients which can be advantageously usedin the practice of this invention are isotonic sodium chloride,cellulose ethers such as hydroxypropylmethylcellulose andhydroxyethylcellulose, polyvinyl alcohol and available artificial teasolutions.

An example of a useful polymeric excipient is a polyoxyethylated castoroil.

Examples of pharmaceutically acceptable membranes which can beadvantageously used in the practice of this invention are microdone, anartificial lipid membrane, polyvinyl alcohol, or methylcellulose.

The cyclosporin A derivatives are advantageously administered topicallyas an ophthalmic drop (solution or suspension) or ophthalmic ointmentcontaining an effective amount of the derivative. Concentrations of 0.01to 50 weight percent, preferably 0.1 to 20 weight percent, of thecyclosporin A derivatives are used in the practice of the presentinvention.

In accordance with a method of the present invention, at least one ofthe cyclosporin A derivatives is administered topically in any quantityrequired to provide the degree of treatment needed. For example, 5microliters to 1 milliliter of a solution, suspension, or ointmentcontaining an effective amount of the cyclosporin A derivative, such as0.01 to 50 weight percent, preferably 0.1 to 20 weight percent, of thecyclosporin A derivative is advantageously used.

Numerous advantages accrue with the practice of the present invention.The method of the present invention is useful in that it can locallyprevent activation of a presystemic response. Topical administration ofthe cyclosporin A derivatives to a patient's tear deficient eyeincreases tear production in the eye. Thus, such treatment furtherserves to correct corneal and conjunctival disorders exacerbated by teardeficiency and KCS, such as corneal scarring, corneal ulceration,inflammation of the cornea or conjunctiva, filamentary keratisis,mucopurulent discharge and vascularization of the cornea. Furthermore,the cyclosporin A derivatives directly decrease the immune response andgranulation and neovascularization.

Further objects of this invention, together with additional featurescontributing thereto and advantages accruing therefrom will be apparentfrom the following hypothetical examples of the invention.

EXAMPLE 1

The Effectiveness of Topical Application of the Cyclosporin ADerivatives of the Invention in Treating an Aqueous Deficient Dry EyeState is Demonstrated as Follows:

A one year old standard female poodle with conjunctivitis exhibits mildaqueous tear deficiency in both eyes. The dog has a Schirmer tear testvalue of 15 mm/minute in the right eye and 10 mm/minute in the left eye.

The Schirmer tear test is a test of aqueous tear production. The testdepends upon observing the extent of wetting a strip of filter paperplaced over the lower lid of an eye for a specified time. Standardizedstrips are commercially available. The strip is folded at a notchedmarking and then placed over the edge of the lateral one-third of theeyelid. The strip is then usually left in place for a period of timewhile the patient looks straight ahead in dim light.

The degree of wetting of the paper is measured in mm from the notch. Forhuman patients, a normal end point is 5 mm of wetting at five minutes.For canine patients, the normal tear production is 14 to 20 mm at oneminute.

The dog is treated with dexamethasone, a corticosteroid sometimes usedas an antiinflammatory agent, by topical administration thereof in botheyes four times daily for nine weeks.

In addition to potential risks associated with such long term use ofthis antiinflammatory agent, it is predicted that the topicaladministration of dexamethasone, even when used in both eyes twice dailyfor nine weeks, may likely be without benefit.

Thus, in this example, the same dog at approximately six years old stillexhibits conjunctivitis in both eyes. Due to the chronic nature of itscondition and possibly due to the dog's normal aging, the dog may nowhave a lower Schirmer tear test value of 3 mm/minute in both eyes.

The same six year old dog is then treated by topical application 2% of a((R)-methylthio-Sar)³-(4′-hydroxy-MeLeu) cyclosporin A derivative offormula I in an olive oil solution in both eyes once daily without anyother medications. After ten days, the dog shows markedly increased tearproduction.

The treatment by topical application of 2% of a((R)-methylthio-Sar)³-(4′-hydroxy-MeLeu) cyclosporin A derivative offormula I in an olive oil solution in both eyes once daily is continuedfor an additional three weeks. At this time, the dog exhibits plentifulaqueous tear production. The treatment is stopped for a period of oneweek and then restarted for a period of one week. After restarting thetreatment, the dog may show even greater increased tear production.

In this case, a dog with chronic tear deficiency in which prior use ofcorticosteroids fails to improve tear secretion shows an increase intear production with topical cyclosporin A derivatives. The increasedtear production may continue only while cyclosporin A derivative therapycontinues. When the treatment is stopped for a week, recurrence of teardeficiency may be found. However, tear production increases to normallevels after the treatment is restarted.

EXAMPLE 2

The Effectiveness of Topical Application of the Cyclosporin ADerivatives of the Invention in Treatment of PhacoanaphylacticEndophthalmitis is Demonstrated as Follows:

In this example, a lens induced granulomatous endophthalmitis (ELGE)model (See Marak, G. E. et al., Ophthal. Res. (1978) 10:30) isreproduced in {fraction (4/8)} control eyes of rats. Eyes treatedtopically with the cyclosporin A derivatives of Formula II uniformlyfail to develop marked cellular infiltration following rupture of thelens capsule. Rats treated conventionally using systemic cyclosporinewill show modest protection compared to untreated rats. Based on aprophylactic effect of topical application of the cyclosporin Aderivatives of formula II against development of ELGE, penetration ofthe globe by the topical cyclosporin A derivatives in therapeutic levelsis indicated.

Eleven female adult Wistar Furth rats are immunized subcutaneously onthree occasions every two weeks with 1 ml of 50:50 mixture of 10 mghomologous lens protein in saline and Freund's complete adjuvant. Twoweeks after the last immunization, the rats are anesthetized withKetamine HCl 10 mg/kg intramuscularly. With the aid of a dissectingmicroscope, a sterile 26 g needle is introduced through the centralcornea and a Z-shaped anterior lens capsule tear is formed bymanipulating the needle in the right eye. Tobrex® ointment is appliedpost operatively and tetracycline 400 mg/liter is added to the drinkingwater.

Four rats serve as controls and receive no antiinflammatory drugs. Fourrats receive 10 mg/kg of 2% cyclosporin orally beginning two hourspost-operatively. Three rats receive 15 μl of 2% of a((R)-(Cyclo)alkylthio-Sar)³-(4′-hydroxy-MeLeu)⁴-cyclosporin A of FormulaII in olive oil applied topically 9-12 times daily for three daysfollowing injury, then four times daily thereafter. After 7 days, theleft eye capsules are torn as above in all rats.

All rats are examined periodically with a slit lamp or dissectingmicroscope. Fourteen days after the initial surgery, all rats areeuthanized with halothane® anesthetic. Both eyes are fixed in formalin,processed by standard methods, and stained with hematoxylin and eosin.

It is predicted that immediately post-operatively, all rats develop aplasmoid aqueous and miosis lasting 48 to 72 hours. Several of the eightuntreated eyes continue to develop severe uveitis beginning withhypopyon and corneal edema. Some of these untreated eyes also developsecondary glaucoma with buphthalmos. Progression continues with thedevelopment of corneal abcessation, neovascularization andpanophthalmitis. Some eyes may progress to a phthesis bulbi.Histopathology of these eyes reveal an aseptic gramulomatouspanophthalmitis. A zonal distribution of neutrophilis and macrophagesoccurs around the ruptured lens capsule where early cataractrous changeswere evident. A cyclictic membrane forms behind the lenses. The anteriorchamber, iris, vitreous humour and retina are densely infiltrated withlymphocytes. On histopathologic examination, several untreated eyes havemoderate, acute anterior uveitis; however, it is predicted that someuntreated eyes may have no inflammation at seven or fourteen days postinjury.

In contrast, none of the six eyes treated with topical((R)-(Cyclo)alkylthio-Sar)³-(4′-hydroxy-MeLeu)⁴-cyclosporin A derivativeof Formula II develop any prolonged or destructive inflammation.

The rats given oral cyclosporine may develop uveitis intermediate inintensity between controlled and topically treated eyes.

EXAMPLE 3

The Effectiveness of Topical Application of the Cyclosporin ADerivatives of the Invention in Treating Uveitis is Demonstrated asFollows:

Sixteen rabbits, 32 eyes are injected intravitreally on day 1 with 500micrograms of human serum albumin. Eight rabbits receive no treatment.The other rabbits receive 10 microliters of 2% of a((R)-(Cyclo)alkylthio-Sar)³-(4′-hydroxy-MeLeu)⁴-cyclosporin A derivativeof Formula II in olive oil applied topically to both eyes four timesdaily beginning 1 hour after albumin injection. The degree ofintraocular inflammation produced is graded clinically three time a weekfor three weeks. The scale used to evaluate the eyes is given below:

Scheme for Grading Uveitis in Animals injected with Human Serum AlbuminClinical Observation 0 +1 +2 +3 +4 Ciliary-scleral injection none tracemild moderate severe Corneal clarity clear trace edema mild edemamoderate severe Iris injection none, pupil trace mild moderate severe,pupil normal fixed Anterior chamber haze clear trace mild moderate, ±Opaque, ± few KP's many KP's Vitreous & retina ChorioretinalChorioretinal fair red poor red no red detail sharp detail visiblereflex reflex reflex but blurred

The degree of inflammation, 1-4 of each regiment of the eye is summed oneach day, giving a possible range of inflammation of 0-20 per day. Amarked difference in clinical severity of inflammation between eyestreated with the cyclosporin A derivative of Formula II and control eyesis found.

In a broader aspect of the present invention, the cyclosporin Aderivatives of the present invention may be useful in treating otherdisorders of the eye, for example a disorder caused by excessive immuneactivity in the anterior segment, posterior segment or the vitreous bodyof an eye, when administered in an amount sufficient to reduce saidimmune activity.

Although there has been hereinabove described a method for oculartreatment using certain cyclosporin A derivatives, in accordance withthe present invention, for the purpose of illustrating the manner inwhich the invention may be used to advantage, it should be appreciatedthat the invention is not limited thereto. Accordingly, any and allmodifications, variations, or equivalent arrangements which may occur tothose skilled in the art, should be considered to be within the scope ofthe present invention as defined in the appended claims.

What is claimed is:
 1. A method for enhancing or restoring lacrimalgland tearing in an eye, the method comprising administering topicallyto the eye, in a pharmaceutically acceptable excipient, a methylthio-substituted or other alkyl thio-substituted cyclosporin Aderivative selected from the group consisting of compounds representedby the general formulas:

wherein Me is methyl; Alk is 2-6C alkylene or 3-6C cycloalkylene; R isOH, COOH, alkoxycarbonyl, —NR₁ R₂ or —N (R₃)—(CH₂)_(n)—NR₁R₂; whereinR₁, R₂ is H, alkyl, 3-6C cycloalkyl, phenyl (optionally substituted byhalo, alkoxy, alkoxycarbonyl, amino, alkylamino or dialkylamino), benzylor saturated or unsaturated heterocyclyl having 5 or 6 members and 1-3heteroatoms; or NR₁R₂ is a 5 or 6 membered heterocycle which may containa further N, O or S heteroatom and may be alkylated; R₃ is H or alkyland n is 2-4; and alkyl moieties contain 1-4C.
 2. The method accordingto claim 1 wherein the compound is administered as a solution,suspension or ointment comprising 0.01 to 50 weight percent of thecompound.
 3. The method according to claim 2 wherein the compound isadministered in an amount of 0.1 to 20 weight percent.
 4. The methodaccording to claim 1 wherein the pharmaceutically acceptable excipientis selected from the group consisting of olive oil, arachis oil, castoroil, polyoxyethylated castor oil, mineral oil, petroleum jelly, dimethylsulphoxide, an alcohol, liposome, silicone fluid and mixtures thereof.5. The method of claim 4 wherein the pharmaceutically acceptableexcipient is dimethyl sulphoxide.
 6. A method for treating a disorderexacerbated by deficient tear production in a patient, the methodcomprising administering topically to the eye, in a pharmaceuticallyacceptable excipient, a methyl thio-substituted or other alkylthio-substituted cyclosporin A derivative selected from the groupconsisting of compounds represented by the general formulas:

wherein Me is methyl; Alk is 2-6C alkylene or 3-6C cycloalkylene; R isOH, COOH, alkoxycarbonyl, —NR₁ R₂or —N(R₃)—(CH₂)_(n)—NR₁R₂; wherein R₁,R₂ is H, alkyl, 3-6C cycloalkyl, phenyl (optionally substituted by halo,alkoxy, alkoxycarbonyl, amino, alkylamnino or dialkylamino), benzyl orsaturated or unsaturated heterocyclyl having 5 or 6 members and 1-3heteroatoms; or NR₁R₂ is a 5 or 6 membered heterocycle which may containa further N, O or S heteroatom and may be alkylated; R₃ is H or alkyland n is 2-4; and alkyl moieties contain 1-4C.
 7. The method accordingto claim 6 wherein the compound is administered as a solution,suspension or ointment comprising 0.01 to 50 weight percent of thecompound.
 8. The method according to claim 7 wherein the compound isadministered in an amount of 0.1 to 20 weight percent.
 9. The methodaccording to claim 6 wherein the pharmaceutically acceptable excipientis selected from the group consisting of olive oil, arachis oil, castoroil, polyoxyethylated castor oil, mineral oil, petroleum jelly, dimethylsulphoxide, an alcohol, liposome, silicone fluid and mixtures thereof.10. The method of claim 9 wherein the pharmaceutically acceptableexcipient is dimethyl sulphoxide.